In estrogen receptor positive (ER+) breast cancer, an elevated mTOR activity causes resistance to conventional chemo- and hormonal therapies. Estrogen and its membrane- associated estrogen receptors are known to contribute to this abnormal mTOR activity independent of their role in transcription. However, the underlying mechanism remains unknown. Recently, arachidonic acid (AA) and its metabolites have been found to serve as key mediators for the non-genomic action of estrogen. In concert with this finding, we have observed a strong correlation between AA level and mTOR activity in tumor samples from breast cancer patients. These observations suggest a potential signaling nexus that links estrogen, AA and mTOR. This exploratory R21 project is proposed to delineate the molecular basis for this novel signaling scheme. Three lines of investigation are planned to test the hypothesis that estrogen activates mTOR through the AA metabolic cascade, including determining: 1) the role of AA metabolic cascade in estrogen-induced mTOR activation, 2) the metabolites of AA involved mTOR regulation, and 3) the mechanism by which the metabolites of AA activate mTOR. Successful completion of the proposed research will not only shed light on a novel signaling mechanism for mTOR activation but also allow further elevation of the therapeutic implication of this signaling mechanism in breast cancer treatment.